The molecular mechanisms linking obesity, insulin resistance, diabetes, cardiovascular diseases and other associated pathologies are not fully understood. In the past decade, studies in many groups, including ours, have illustrated the importance of inflammation in metabolic disease, particularly in obese adipose tissue. Macrophages and their interactions with adipocytes in the adipose tissue are potentially involved in this process in this process through the integration of lipid signals with inflammatory networks. In this project, we propose to focus on the function and mechanisms of action of fatty acid binding proteins (FABPs) that integrate macrophage and adipocyte function and significantly contribute to metabolic diseases associated with obesity. Adipocyte/macrophage FABPs, aP2 and mal1, coordinately regulate adipocyte and macrophage responses and mice with targeted mutations in these genes exhibit marked protection against insulin resistance, type 2 diabetes, fatty liver disease, atherosclerosis, and asthma. Recently, our lab and other groups demonstrated that aP2 function is highly relevant to human disease by discovering the links between genetic variation at aP2 locus and the risk for type 2 diabetes and cardiovascular disease. New and exciting emerging data both in our group and elsewhere also demonstrated that aP2 is secreted from adipocytes and systemic aP2 levels are strongly associated with obesity, type 2 diabetes and cardiovascular disease in humans. Furthermore, these FABPs regulate the secretion of additional proteins from the adipose tissue and play a significant role in mediating lipotoxic responses in target cells, including macrophages. In the studies planned in this proposal, we will address the biological functions of the soluble FABP, focusing primarily on aP2, characterize other FABP-regulated secreted products in adipose tissue and explore the molecular mechanisms by which aP2 mediate lipotoxicity, with a focus on lipid-induced endoplasmic reticulum stress and related signaling and transcriptional networks. In these studies we will also utilize a newly developed chemical tool to inhibit aP2 which can mimic the metabolic consequences of genetic deficiency of FABPs in cells and in whole animals. Studying the biology and mechanisms of action of adipocyte/macrophage FABPs will be insightful in building models to understand how metabolic disease cluster around obesity and mechanistically linked to each other and carry this knowledge to human disease for preventive and therapeutic applications.